1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea (gedatricib) and combinations thereof for use in the treatment of cancer

Abstract

A method for treating cancer in a human subject is provided. The method includes the steps of selecting a subject in need of cancer treatment, administering to the subject a therapeutically effective amount of gedatrisib at least once a week for a period of three weeks, discontinuing administration of gedatrisib for a period of one week, and resuming administration of gedatrisib at least once a week after the discontinuation period. The administration for a period of at least three weeks and the discontinuation for a period of at least one week constitute one cycle, and the cycle is repeated at least two times.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 285,327, filed December 2, 2021, and U.S. Provisional Application No. 63 / 225,707, filed July 26, 2021, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present invention relates to methods for treating cancer in a patient by administering 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea. [Background technology]

[0003] background 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, also known as gedatricisib, has the chemical structure: [ka] has.

[0004] 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is an inhibitor of PI3 kinase and mTOR useful in the treatment of cancer. Mammalian target of rapamycin (mTOR) is a cell signaling protein that regulates tumor cell responses to nutrients and growth factors, as well as controlling tumor blood supply through its action on vascular endothelial growth factor (VEGF). Inhibitors of mTOR starve cancer cells and shrink tumors by blocking the action of mTOR. All mTOR inhibitors bind to the mTOR kinase. This has at least two important effects. First, mTOR is a downstream mediator of the PI3K / Akt pathway. The PI3K / Akt pathway is thought to be overactivated in many cancers, which may account for the wide range of responses from various cancers to mTOR inhibitors. Overactivation of upstream pathways will usually lead to overactivation of mTOR kinase as well. However, in the presence of mTOR inhibitors, this process is blocked. This blocking action prevents mTOR from signaling downstream pathways that control cell growth. Overactivation of the PI3K / Akt kinase pathway is often associated with mutations in the PTEN gene, which is common in many cancers and may help predict which tumors will respond to mTOR inhibitors. The second major effect of mTOR inhibition is antiangiogenesis through reducing VEGF levels.

[0005] Breast cancer is the most common form of cancer and the leading cause of cancer deaths in women worldwide. Currently, there are three main different treatment modalities for the systemic treatment of breast cancer, and the applicability of these different treatment options depends substantially on the receptor status of the patient (Bernard-Marty et al., 2004). Endocrine and biological therapies require the presence of their respective receptors on the cancer cells, whereas cytotoxic chemotherapy is independent of their identified receptors.

[0006] In patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer, endocrine therapy alone or in combination with cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitors, PI3K-α inhibitors, or mTOR inhibitors is usually the treatment of choice (NCCN Treatment Guidelines for Breast Cancer, 2021).

[0007] Selective ER modulators (tamoxifen), selective ER degraders (fulvestrant), and aromatase inhibitors (AIs) are the established standard of care in women with HR+ / HER2- metastatic breast cancer (mBC). Choosing between these regimens when treating mBC depends on the type and duration of prior endocrine therapy treatment, as well as the time since completion of prior endocrine therapy. Despite the well-known efficacy of these treatments as first-line treatment in women without visceral crisis, most patients develop endocrine resistance and treatment failure. Primary endocrine resistance is defined as recurrence during the first 2 years of prior endocrine therapy, or progressive disease within the first 6 months of first-line endocrine therapy for mBC. Secondary resistance exists if (1) recurrence occurs after the first 2 years of adjuvant endocrine therapy, (2) recurrence occurs within 12 months of completion of adjuvant endocrine therapy, or (3) progressive disease occurs more than 6 months after initiation of endocrine therapy for mBC.

[0008] Endocrine resistance involves several mechanisms, including dysregulation of multiple components of the ER pathway (abnormal ER expression, overexpression of ER coactivators, and downregulation of corepressors), altered regulation of signaling molecules involved in the cell cycle or cell survival, and activation of escape pathways that may provide for cell replication.

[0009] One common mechanism of resistance to endocrine therapy is activation of the cyclin-dependent kinase 4 and 6 (CDK4 / 6) pathway. These kinases drive cell cycle progression and division. Inhibiting CDK4 / 6 activation prevents estrogen from activating the cyclin D1-CDK4 / 6-Rb complex, thus blocking a key mechanism of resistance to endocrine therapy. The resulting cell cycle arrest induces a significant delay in tumor progression.

[0010] CDK 4 / 6 inhibitors were first introduced in 2015. Administering endocrine therapy in combination with an oral CDK4 / 6 inhibitor results in improved clinical efficacy when compared to endocrine therapy as monotherapy. In two randomized double-blind clinical trials, treatment of patients with HR+ / HER2- advanced breast cancer with a combination of palbociclib and either letrozole or fulvestrant showed a significant increase in median progression-free survival (PFS) duration for patients who received palbociclib in combination with either letrozole or fulvestrant compared to patients who received letrozole or fulvestrant as single agents (Turner et al., N. Engl. J. Med. 373:209-19 (2015); Finn et al., N. Engl. J. Med. 375:1925-36 (2016). These patients had previously progressed on or after prior endocrine therapy.

[0011] Another common mechanism of resistance to endocrine inhibitors is activation of the PI3K pathway, a key intracellular pathway that regulates cell growth and metabolism. Approximately one-third of HR+ breast cancer tumors that are resistant to endocrine therapy harbor activating mutations in the catalytic subunit of PI3K, termed PIK3CA. The use of fulvestrant in combination with alpelisib, an oral PI3K-α inhibitor approved by the FDA in May 2019, has demonstrated improved clinical efficacy in patients whose tumors harbor PIK3CA mutations and who have not yet been treated with a CDK4 / 6 inhibitor. These patients had previously progressed on or after prior endocrine therapy. Similar to CDK4 / 6 and PI3K, the mTOR pathway has also been identified as a mechanism of resistance to endocrine therapy. Everolimus is an mTOR inhibitor currently FDA approved for the treatment of HR+ / HER2- advanced breast cancer in combination with the AI ​​exemestane. Everolimus has also shown clinical benefit in combination with fulvestrant. These patients have previously progressed on or after prior AI therapy. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Turner et al., N. Engl. J. Med. (2015) 373:209–19 [Non-Patent Document 2] Finn et al., N. Engl. J. Med. (2016) 375:1925~36 Summary of the Invention [Means for solving the problem]

[0013] Despite the availability of new therapeutic options, women with HR+ / HER2- breast cancer still face poor long-term prognosis, especially those whose cancer has spread to other organs and those that are resistant to endocrine therapy. Thus, there is a need for breast cancer treatments in patients who have not been successfully treated with endocrine therapy.

[0014] overview Provided herein is a method for treating cancer in a patient.The method comprises administering gedatolisib intravenously to a patient once a week for three weeks, followed by one week without gedatolisib.This administration regimen, which constitutes a 28-day cycle (three weekly doses of gedatolisib, followed by one week of gedatolisib rest), is then repeated as necessary.The cyclic administration of gedatolisib using a cycle of three weeks on and one week off has been shown to be more successful in treating cancer than the administration of gedatolisib in a weekly or non-cyclical manner.

[0015] Thus, in one embodiment, the present invention relates to a method for treating cancer in a human subject, comprising the steps of: selecting a human subject in need of cancer treatment; administering to the human subject a therapeutically effective amount of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, at least once a week for a period of three weeks; discontinuing administration of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, for a period of one week; and resuming administration of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, after the discontinuance period, at least once a week. The administration for a period of at least three weeks and the discontinuance for a period of at least one week constitute one cycle, and the cycle is repeated at least two times.

[0016] In some embodiments, the resumed administration of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, occurs at least once a week for a period of 3 weeks. The cycles of administration can occur for at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles, at least 9 cycles, or at least 10 cycles, or more. In further embodiments, gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, is administered at a dose of 180 mg once a week.

[0017] In some embodiments, the method includes co-administering a CDK 4 / 6 inhibitor to a human subject at least once a week for a period of 3 weeks, discontinuing administration of the CDK 4 / 6 inhibitor for a period of 1 week, and resuming administration of the CDK 4 / 6 inhibitor for at least 1 week after the discontinuation period. The cycle of administration and discontinuation of the CDK 4 / 6 inhibitor is repeated for at least 2 cycles. In further embodiments, the CDK 4 / 6 is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, ribiciclib, and combinations thereof. Preferably, the CDK 4 / 6 inhibitor is palbociclib. Furthermore, palbociclib can be administered at a dose of 125 mg per day.

[0018] In some embodiments, the method comprises co-administering an estrogen receptor antagonist to a human subject.Preferably, the estrogen receptor antagonist is fulvestrant.Fulvestrant can be administered at a dose of 500mg every 2 weeks.In addition, fulvestrant can be administered at a dose of 500mg every 4 weeks.In some cases, fulvestrant is first administered at a dose of 500mg every 2 weeks, and then reduced to a dose of 500mg every 4 weeks.

[0019] A further aspect of the present invention relates to a method of treating cancer in a human subject, comprising the steps of: selecting a human subject in need of cancer treatment; administering to the human subject a therapeutically effective amount of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor at least once a week for a period of three weeks; discontinuing administration of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor for a period of one week; and resuming administration of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor at least once a week after the discontinuance period. The administration for a period of at least three weeks and the discontinuance for a period of at least one week constitute one cycle, and the cycle is repeated for at least two cycles.

[0020] In some embodiments, the resumed administration of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, and the CDK 4 / 6 inhibitor occurs at least once a week for a period of three weeks.

[0021] Another aspect of the invention relates to a method of treating cancer in a human subject, comprising the steps of: selecting a human subject in need of cancer treatment; administering to the human subject a therapeutically effective amount of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor at least once a week for a period of three weeks; discontinuing administration of the gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor for a period of one week; and resuming administration of the gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor after the discontinuance period at least once a week, wherein the administration for a period of at least three weeks and the discontinuance for a period of at least one week constitute one cycle, and the cycle is repeated for at least two cycles; and administering to the human subject an estrogen receptor antagonist.

[0022] In some embodiments, the target cancer is solid cancer.Exemplary solid cancer includes but is not limited to breast cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, prostate cancer, testicular cancer, penile cancer, lung cancer, colorectal cancer, melanoma, bladder cancer, brain / CNS cancer, esophageal cancer, gastric cancer, head / neck cancer, kidney cancer, liver cancer, pancreatic cancer, and sarcoma.

[0023] In some embodiments, the solid cancer of the subject is a hormone-dependent cancer. Exemplary hormone-dependent cancers include, but are not limited to, breast cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, prostate cancer, testicular cancer, and penile cancer. In some embodiments, the hormone-dependent cancer is breast cancer. In further embodiments, the breast cancer of the subject is metastatic, hormone-resistant, estrogen receptor positive, estrogen receptor negative, progesterone receptor negative, progesterone receptor positive, triple negative, HER2 positive, or HER2 negative breast cancer. Breast cancer can also be either basal or luminal subtype. In further embodiments, the human subject is a premenopausal or postmenopausal female patient.

[0024] In some embodiments, the human subject has failed a prior treatment for cancer in less than 12 months (e.g., less than 6 months). In some embodiments, the human subject has failed two or more prior treatments for cancer. The failed prior treatments can be endocrine or non-endocrine treatments for cancer. In one embodiment, the human subject has failed at least one endocrine treatment for cancer. In one embodiment, the human subject has failed at least one non-endocrine treatment for cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Detailed Description Disclosed herein is a method for treating cancer (e.g., breast cancer) in a human patient. The method comprises administering to the patient a therapeutically effective amount of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, at least once a week for a period of three weeks, followed by a period of one week without administering gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof. The method constitutes a 28-day cycle (three doses of gedatrisib administered every week, one week off gedatrisib), which is repeated for at least two cycles. Surprisingly, the treatment of cancer patients using this cyclic administration method has been found to be more successful than the use of gedatrisib in a non-cyclic dosing regimen.

[0026] In order to make this description more easily understandable, certain terms are first defined. Further definitions are described throughout the detailed description. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0027] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise. The use of "or" or "and" means "and / or" unless indicated otherwise.

[0028] As used herein, when referring to measurable values, e.g., amounts, time periods, etc., the term "about" encompasses up to ±10% variation from the specified value. Unless otherwise indicated, all numbers expressing quantities with respect to ingredients, properties, e.g., molecular weight, reaction conditions, etc. used herein shall be understood to be modified by the term "about."

[0029] Gedatolicib is a small molecule that inhibits phosphatidylinositol-3 kinase and the mammalian target of rapamycin, and is a promising small molecule for the treatment of cancer. Phosphatidylinositol-3 kinase (PI3K) is an enzyme that phosphorylates the 3-position of the inositol ring of phosphatidylinositol (D. Whitman et al., (1988)). There are multiple PI3K subtypes, and three major subtypes of PI3K have been identified based on their in vitro substrate specificity. These three are termed class I (a and b), class II, and class III (B. Vanhaesebroeck, (1997)).

[0030] The phosphoinositide 3-kinase signaling pathway is one of the most highly mutated systems in human cancer. PI3K is a member of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group on phosphatidylinositols or phosphoinositides. The PI3K family includes 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation. Class I PI3Ks (p110α, p110β, p110δ, and p110γ) are typically activated by tyrosine kinases or G-protein-coupled receptors to generate phosphatidylinositol (3,4,5)-triphosphate (PIP3), which engages downstream effectors such as those in the AKT / PDK1 pathway, mTOR, Tec family kinases, and Rho family GTPases. Class II and III PI3Ks play an important role in intracellular trafficking through the synthesis of phosphatidylinositol 3-bisphosphonate (PI(3)P) and phosphatidylinositol (3,4)-bisphosphonate (PI(3,4)P2). PI3Ks are protein kinases that control cell growth (mTORC1) or monitor genome integrity (ATM, ATR, DNA-PK, and hSmg-1).

[0031] There are four mammalian isoforms of class I PI3K: PI3K-α, β, δ (class Ia PI3K), and PI3K-γ (class Ib PI3K). These enzymes catalyze the production of PIP3, leading to the activation of downstream effector pathways important for cell survival, differentiation, and function. PI3K-α and PI3K-β are widely expressed and are important mediators of signaling from cell surface receptors. PI3K-α is the isoform most frequently found mutated in cancer and has a role in insulin signaling and glucose homeostasis (Knight et al., (2006); Vanhaesebroeck et al., (2010)). PI3K-β is activated in cancers with deletions of phosphatase and tensin homolog (PTEN). Both isoforms are targets for small molecule therapeutics in development for cancer.

[0032] PI3K-δ and -γ are preferentially expressed in leukocytes and are important for leukocyte function. These isoforms also contribute to the development and maintenance of hematological malignancies (Vanhaesebroeck et al., (2010); Clayton et al., (2002); Fung-Leung, (2011); Okkenhaug et al., (2002)). PI3K-δ is activated by cellular receptors (e.g., receptor tyrosine kinases) through interaction with the Sarc homology 2 (SH2) domain of the PI3K regulatory subunit (p85) or through direct interaction with RAS.

[0033] Selectivity over other related kinases is also an important consideration for the development of PI3K inhibitors. Although selective inhibitors may be preferred to avoid unwanted side effects, there are reports that inhibition of multiple targets in the PI3K / Akt pathway (e.g., PI3Kα and mTOR [mammalian target of rapamycin]) may result in greater efficacy.

[0034] Mammalian target of rapamycin (mTOR) is a cell signaling protein that regulates tumor cell responses to nutrients and growth factors, as well as controlling tumor blood supply through its action on vascular endothelial growth factor VEGF. Inhibitors of mTOR starve cancer cells and shrink tumors by blocking the action of mTOR. All mTOR inhibitors bind to the mTOR kinase. This has at least two important effects. First, mTOR is a downstream mediator of the PI3K / Akt pathway. The PI3K / Akt pathway is thought to be overactivated in many cancers and may be responsible for the wide range of responses from various cancers to mTOR inhibitors. Overactivation of upstream pathways would normally cause overactivation of mTOR kinase as well. However, in the presence of mTOR inhibitors, this process is blocked. This blocking action prevents mTOR from signaling downstream pathways that control cell growth. Hyperactivation of the PI3K / Akt kinase pathway is often associated with mutations in the PTEN gene, which are common in many cancers and may help predict which tumors will respond to mTOR inhibitors.A second major effect of mTOR inhibition is antiangiogenesis through reducing VEGF levels.

[0035] As used herein, the terms "gedatrisib" and "1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea" refer to the same compound and may be used interchangeably. In some embodiments of the present invention, pharma- ceutically acceptable salts, solvates, or esters of gedatrisib may be used in methods of treating cancer, as known to those skilled in the art.

[0036] Representative "pharmaceutically acceptable salts" include, for example, water soluble and water insoluble salts, such as acetate, aluminum, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzathine (N,N'-dibenzylethylenediamine), benzenesulfonate, benzoate, bicarbonate, bismuth, bisulfate, bitartrate, borate, bromide, butyrate, calcium, edetate calcium, camsylate (camphorsulfonate), carbonate, chloride, choline, citrate, clavulariate, diethanolamine, ... Amine, dihydrochloride, diphosphate, edetate, edisylate (camphorsulfonate), esylate (ethanesulfonate), ethylenediamine, fumarate, gluceptate (glucoheptonate), gluconate, glucuronate, glutamate, hexafluorophosphate, hexylresorcinate, hydrabamine (N,N'-bis(dehydroabietyl)ethylenediamine), hydrobromide, hydrochloride, hydroxynaphthoate, 1-hydroxy-2-naphthoate, 3-hydroxy-2- Naphthoate, iodide, isethionate (2-hydroxyethanesulfonate), lactate, lactobionate, laurate, lauryl sulfate, lithium, magnesium, malate, maleate, mandelate, meglumine (1-deoxy-1-(methylamino)-D-glucitol), mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate Salts (4,4'-methylenebis-3-hydroxy-2-naphthoate or embonate), pantothenate, phosphate, picrate, polygalacturonate, potassium, propionate, p-toluenesulfonate, salicylate, sodium, stearate, subasetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, theoclate (8-chloro-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione), trieth iodide, tromethamine (2-amino-2-(hydroxymethyl)-1,3-propanediol), valerate, and zinc salts.

[0037] Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids, and boronic acids.

[0038] Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or from 1 to about 100, or from 1 to about 10, or from 1 to about 2, 3, or 4 solvent or water molecules.

[0039] The term "inhibit" or "reduce" as used herein refers to any statistically significant decrease in biological activity, including partial or complete blocking of activity.For example, "inhibit" or "reduce" can refer to a statistically significant decrease in biological activity of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100%.The term "inhibit" or "block" (e.g., referring to the inhibition / blocking of binding or activity) is used interchangeably and includes both partial and complete inhibition / blocking.

[0040] As used herein, the term "subject" includes any human or non-human animal.For example, the methods and compositions described herein can be used to treat subjects (e.g., human patients) with cancer.Preferably, the subject is a human with breast cancer and has experienced cancer progression during a previous treatment (e.g., endocrine treatment) for less than 12 months (e.g., less than 6 months).

[0041] "Therapeutically effective amount" means an amount of gedatrisib or other active agent described herein that is effective to provide a therapeutic effect when administered to a subject.

[0042] As used herein, "administering" refers to the physical introduction of a composition containing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Preferred routes of administration of the therapeutic agents described herein include intravenous, intraperitoneal, intramuscular, subcutaneous, spinal, or other parenteral routes of administration, such as by injection or infusion. As used herein, the phrase "parenteral administration" refers to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, and in vivo electroporation. Alternatively, the antibodies described herein can be administered via non-parenteral routes, such as topical, epithelial, or mucosal routes of administration, for example, intranasally, orally, vaginally, rectally, sublingually, or topically. Also, administration can be carried out, for example, once, multiple times, and / or over one or more extended periods of time.

[0043] As used herein, the terms "treatment", "treating", "treat" and the like refer to alleviating or reducing the severity of at least one symptom or indication, eliminating the cause of a symptom either temporarily or permanently, or obtaining a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, reduction in the extent of a condition, disorder, or disease, stabilization (i.e., not worsening) of the condition, disorder, or disease state, delay in onset or slowing down the progression of the condition, disorder, or disease, amelioration of the condition, disorder, or disease state, and remission (partial or complete), whether detectable or undetectable, or improvement or amelioration of the condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival in the absence of treatment. Treatment may result in a partial response (PR) or a complete response (CR).

[0044] "Endocrine treatment" or "hormonal treatment" (sometimes referred to as "anti-hormonal treatment") refers to treatments that target hormone signaling, such as hormone inhibition, hormone receptor inhibition, use of hormone receptor agonists or antagonists, use of scavenger or orphan receptors, use of hormone derivatives, and interference with hormone production. Specific examples are tamoxifen therapy, which modulates estrogen receptor signaling, or aromatase treatment, which interferes with steroid hormone production.

[0045] The term "failed prior treatment" refers to a subject undergoing treatment for cancer experiencing cancer progression during treatment, for example, within a specified period of treatment (e.g., within 12 months or within 6 months of beginning treatment). The term "progression" of cancer typically refers to an increase in growth and / or spread (e.g., metastasis), as measured by means established in the art for assessing cancer growth and / or spread, including, but not limited to, body scans (e.g., MRI scans, PET scans, CAT scans, etc.), biopsies, and / or biomarker measurements. In some embodiments, progression is defined as an increase in the sum of diameters of targeted measurable lesions (e.g., tumors) of at least 20% over the minimum observed sum or baseline sum of diameters, with the minimum absolute increase being at least 5 mm.

[0046] The terms "therapeutic modality", "treatment style", "schedule", "regimen" and "treatment regimen" refer to the chronologically sequential or simultaneous administration of antitumor drugs, and / or antivascular drugs, and / or immune stimulants, and / or blood cell proliferation agents, and / or radiation therapy, and / or hyperthermia, and / or hypothermia for the treatment of cancer. These administrations may be performed in an adjuvant and / or neoadjuvant manner. The composition of such "protocols" may vary in the doses of single agents, the time frames of application, and the frequency of administration within a defined therapeutic window.

[0047] The term "cytotoxic chemotherapy" refers to a variety of treatment modalities that affect cell proliferation and / or survival. Treatment may include administration of alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, and other antitumor agents, including monoclonal antibodies and kinase inhibitors. In particular, cytotoxic treatment may involve taxane treatment. Taxanes are plant alkaloids that block cell division by preventing microtubule function. The prototype taxane is paclitaxel, a natural product commonly known as taxol, originally derived from the bark of the Pacific yew tree. Docetaxel is a semisynthetic analog of paclitaxel. Taxanes enhance microtubule stability and prevent anaphase chromosome segregation.

[0048] The various aspects described herein are described in further detail in the following subsections.

[0049] I. Gedatlisib Provided herein is a method for treating cancer by administering a therapeutically effective amount of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, in a cyclical manner to a subject (e.g., a human subject who has failed a prior treatment for cancer (e.g., an endocrine treatment for cancer) for less than 12 months (e.g., 6 months). Cyclic administration can include, for example, administering gedatrisib to a subject for three weeks, followed by a one-week administration break. This cycle can be repeated multiple times as necessary to obtain the desired results.

[0050] Gedatolisib is a highly potent pan-class I isoform PI3K / mTOR inhibitor (NCT02626507, April 24, 2020). The chemical synthesis of gedatolisib is disclosed in U.S. Patent Nos. 8,039,469, 8,217,036, 8,445,486, 8,575,159, 8,748,421, 8,859,542, 9,174,963, and 10,022,381, which are incorporated by reference in their entireties. Gedatolisib may be prepared in a crystalline form and is chemically and physically stable in this form for up to three years at 25° C. and 60% relative humidity (RH). However, the free base is insufficiently water soluble to allow for the preparation of an aqueous solution formulation suitable for intravenous or parenteral administration at the required therapeutic dosage levels. Thus, formulations that allow for therapeutic dosage levels were developed.

[0051] Pharmaceutical formulations containing therapeutic dosage levels of gedatrisib are known in the art, including aqueous intravenous formulations as well as nanoparticulate formulations.

[0052] PCT Publication No. WO2016097949 discloses an aqueous intravenous formulation of gedatricisib with lactic acid and / or orthophosphoric acid that forms a clear solution free of particulates. The formulation includes gedatricisib, lactic acid, and water. Gedatricisib has a concentration of less than 6 mg / ml (preferably about 5 mg / ml) in the solution, and sufficient lactic acid is present (preferably at least 2.5 molar equivalents) to provide a clear solution. Gedatricisib forms a 1:1 (molar equivalent) lactate salt with lactic acid. Thus, the formulation can be prepared using gedatricisib free base or using the lactate salt of gedatricisib.

[0053] Formulations with orthophosphoric acid include gedatricisib, orthophosphoric acid, and water, where gedatricisib is present in a solution concentration of less than 4 mg / ml (preferably 3.0-3.5 mg / ml) and sufficient orthophosphoric acid is present to provide a clear solution (preferably at least 5 molar equivalents).

[0054] A formulation comprising gedatricisib and a cyclodextrin is disclosed in PCT Publication No. WO2019234632. The aqueous pharmaceutical formulation comprises gedatricisib or a pharma-ceutically acceptable organic or inorganic acid salt thereof, a pharma-ceutically acceptable organic or inorganic acid that is not a sulfonic acid, a pharma-ceutically acceptable beta- or gamma-cyclodextrin, and water. The gedatricisib is present in a solution concentration of at least 6 mg / ml, and the solution is clear.

[0055] The pharma- ceutically acceptable organic acids (including salts thereof) used are lactic acid, tartaric acid, malic acid, citric acid, succinic acid, acetic acid, or maleic acid. The acids may be used in their racemic form or, where applicable, in single stereoisomeric form (or mixtures thereof). Examples of pharma- ceutical acceptable beta-cyclodextrins are 2-hydroxypropyl-beta-cyclodextrin, and sulfobutylether-β-cyclodextrin (SBECD). Examples of such pharma- ceutical acceptable gamma-cyclodextrins are gamma-cyclodextrin and 2-hydroxypropyl-gamma-cyclodextrin. The preferred amount of pharma- ceutical acceptable beta or gamma-cyclodextrin for use in the formulation is 2-30% weight / volume, 5-20% weight / volume, or 15-30% weight / volume, preferably about 20% weight / volume or about 25% weight / volume. Preferably, the amount of pharma-ceutically acceptable beta or gamma-cyclodextrin for use in the formulations of the present invention is about 20% weight / volume.

[0056] Formulations containing gedatrisib and methanesulfonic acid and / or ethanesulfonic acid are disclosed in PCT Publication No. WO2019038657.

[0057] The formulation comprises gedatrisib, or a methanesulfonate salt thereof, methanesulfonic acid, and water. Gedatrisib is present in a solution concentration of less than 35 mg / ml or up to 30 mg / ml (preferably 6-30 mg / ml), and sufficient methanesulfonic acid is present to provide a clear solution. Another formulation disclosed is gedatrisib, or an ethanesulfonate salt thereof, ethanesulfonic acid, and water. Gedatrisib is present in a solution concentration of less than 35 mg / ml or up to 30 mg / ml (preferably 6-30 mg / ml), and sufficient ethanesulfonic acid is present to provide a clear solution.

[0058] The use of methanesulfonic acid and ethanesulfonic acid allows for the achievement of solution concentrations of gedatricisib of up to 30 mg / ml for aqueous pharmaceutical formulations that are suitable for intravenous or parenteral administration to patients, i.e., clear, essentially particle-free solutions.

[0059] In the above aqueous formulations, a solution concentration of gedatricisib of at least 6 mg / ml is desirable to allow for dose administration to subjects using the single vial presentation of the marketed drug product. Lyophilized drug products (for reconstitution) containing less than 6 mg / ml of drug product solution require multiple vials to deliver the required therapeutic dose. A multiple vial approach to dose delivery is not desirable given current regulatory expectations for these product types.

[0060] Any of the above formulations can be freeze-dried to obtain a lyophilized solid composition, and a bulking agent may be added to the formulation before the start of the freeze-drying process. The bulking agent may be absent if the formulation of the present invention does not contain a pharma-ceutically acceptable beta or gamma-cyclodextrin. The bulking agent's main function is to provide structural integrity to the freeze-dried solid without disintegration, thereby allowing rapid reconstitution upon constitution of the aqueous formulation prior to administration, which should also facilitate efficient lyophilization. Bulking agents are typically used when the total mass of solutes in the formulation is less than 2g / 100ml. Bulking agents may also be added to achieve isotonicity with blood. The bulking agent may be selected from sugars, sugar alcohols, amino acids, or polymers, or may be a mixture of any two or more of these. Preferably, the bulking agent is a sugar or sugar alcohol, or a mixture thereof. Preferably, the sugar is sucrose. Preferably, the sugar alcohol is mannitol. Constitution of the lyophilized solid composition may be achieved using an appropriate amount of water and / or an aqueous solution of a suitable tonicity adjusting agent to ensure that a clear solution is obtained.

[0061] Therapeutic agents that contain at least one basic nitrogen atom (i.e., therapeutic agents that contain protonatable nitrogen), such as gedatricisib, represent an important group of therapeutic agents. However, nanoparticle formulations of this class of drugs are often hindered by undesirable properties, such as unfavorable burst release profile and poor drug loading. PCT Publication No. WO2015138835 discloses therapeutic nanoparticles of gedatricisib that control the release rate of the therapeutic agent.

[0062] The therapeutic nanoparticles comprise gedatricisib (preferably in an amount of about 1-20 weight percent), a substantially hydrophobic acid, and a polymer selected from a diblock poly(lactic acid)-poly(ethylene)glycol copolymer or a diblock poly(lactic acid-co-glycolic acid)-poly(ethylene)glycol copolymer, and combinations thereof. The molar ratio of the substantially hydrophobic acid to gedatricisib ranges from about 0.25:1 to about 2:1, and the pK of protonated gedatricisib is preferably about 0.05:0 to about 0.2:0. a is the pK of the hydrophobic acid a At least about 1.0 pK higher a Unit high. The hydrophobic acid and gedatricisib form a hydrophobic ion pair in the therapeutic nanoparticle. In addition, the nanoparticles may contain targeting ligands that can increase target binding (cell binding / target uptake), making the nanoparticles target specific.

[0063] Generally, "nanoparticle" refers to any particle having a diameter less than 1000 nm. Preferably, therapeutic nanoparticles may have a diameter ranging from 60 to 120 nm. For example, nanoparticles may have a diameter ranging from about 60 nm, about 70 nm, about 80 nm, about 90 nm, about 100 nm, or about 110 nm up to about 70 nm, about 80 nm, about 90 nm, about 100 nm, about 110 nm, or about 120 nm.

[0064] As used herein, a "substantially hydrophobic acid" is an acid that has a pKa in water of about -1.0 to about 5.0. Preferably, a substantially hydrophobic acid has a pKa in water of about 2.0 to about 5.0. Exemplary substantially hydrophobic acids include, but are not limited to, fatty acids. For example, the fatty acid may be a saturated fatty acid, including, but not limited to, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, behenic acid, tricosylic acid, lignoceric acid, pentacosylic acid, cerotic acid, heptacosylic acid, montanic acid, nonacosylic acid, melissic acid, henatriacontylic acid, laceroic acid, psyllic acid, geddic acid, ceroplastic acid, hexatriacontylic acid, or combinations thereof. In addition, the fatty acid may be an omega-3 fatty acid, including but not limited to hexadecatrienoic acid, alpha-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, or combinations thereof.The fatty acid may also be an omega-6 fatty acid, including but not limited to linoleic acid, gamma-linolenic acid, eicosadienoic acid, dihomo-gamma-linolenic acid, arachidonic acid, docosadienoic acid, adrenic acid, docosapentaenoic acid, tetracosatetraenoic acid, tetracosapentaenoic acid, or combinations thereof.The fatty acid may also be an omega-9 fatty acid, including but not limited to oleic acid, eicosenoic acid, mead acid, erucic acid, nervonic acid, or combinations thereof.The fatty acid may also be a polyunsaturated fatty acid, including, but not limited to, rumenic acid, a-calendic acid, β-calendic acid, jacaric acid, a-eleostearic acid, β-eleostearic acid, catarpic acid, punicic acid, rumelenic acid, a-parinaric acid, β-parinaric acid, bosseopentaenoic acid, pinolenic acid, podocarpic acid, or combinations thereof.

[0065] Alternatively, the hydrophobic acid may be a bile acid, for example, in some embodiments, the bile acid may include, but is not limited to, chenodeoxycholic acid, ursodeoxycholic acid, deoxycholic acid, hycholic acid, beta-muricholic acid, cholic acid, lithocholic acid, amino acid conjugated bile acids, or combinations thereof.

[0066] Alternatively, the hydrophobic acid can include, but is not limited to, dioctyl sulfosuccinic acid, 1-hydroxy-2-naphthoic acid, dodecyl sulfuric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, pamoic acid, undecanoic acid, or combinations thereof.

[0067] The nanoparticles can be combined with a pharma- ceutically acceptable carrier to form a pharmaceutical composition. As will be appreciated by those of skill in the art, the carrier can be selected based on the route of administration, the location of the target tissue, the time course of drug delivery, and the like.

[0068] Nanoparticle pharmaceutical compositions can be administered to patients or subjects by any means known in the art, including oral and parenteral routes.Nanoparticle compositions can be administered by injection (e.g., intravenous, subcutaneous, or intramuscular, intraperitoneal injection), rectal, vaginal, topical (as by powder, cream, ointment, or drops), or inhalation (as by spray).

[0069] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids, for example, oleic acid, are used in injectable preparations. In one embodiment, the conjugate of the present invention is suspended in a carrier fluid that includes 1% (weight / volume) sodium carboxymethylcellulose and 0.1% (volume / volume) Tween® 80. The injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0070] The solid dosage form for oral administration includes capsules, tablets, pills, powders, or granules. In such solid dosage forms, the encapsulated or non-encapsulated conjugates contain at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) solution retarders. (f) absorption enhancers, such as quaternary ammonium compounds, (g) wetting agents, such as cetyl alcohol and glycerol monostearate, (h) absorbents, such as kaolin and bentonite clay, and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0071] It will be understood that the exact dosage of the nanoparticles containing gedatricisib will be chosen by the individual physician in light of the patient to be treated, and generally, the dosage and administration will be adjusted to provide the patient being treated with an effective amount of gedatricisib nanoparticles. As used herein, the "effective amount" of the nanoparticles containing gedatricisib refers to the amount necessary to induce the desired biological response. As will be understood by those skilled in the art, the effective amount of the nanoparticles containing gedatricisib can vary depending on factors such as the desired biological endpoint, the target tissue, the route of administration, etc. For example, the effective amount of the nanoparticles can be an amount that results in a reduction in tumor size by a desired amount over a desired period of time. Additional factors that may be considered include the severity of the disease state, the age, weight, and sex of the patient being treated, diet, time and frequency of administration, drug combinations, reaction sensitivity, and tolerance / response to the treatment.

[0072] Aqueous pharmaceutical formulations of gedatrisib suitable for intravenous administration, such as those described above, generally have a pH of 3-9. However, in certain circumstances, lower pH values ​​are acceptable. The pH can range from about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 up to about 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9. Preferably, the pH is 3-8 or 4-8.

[0073] The weekly dose of gedatrisib administered by intravenous route for the treatment of cancer using the above-mentioned formulations is preferably in the range of 100-400 mg / ml per week. For example, the dose may be about 100 mg / ml per week, about 110 mg / ml per week, about 120 mg / ml per week, about 130 mg / ml per week, about 140 mg / ml per week, about 150 mg / ml per week, about 160 mg / ml per week, about 170 mg / ml per week, about 180 mg / ml per week, about 190 mg / ml per week, about 200 mg / ml per week, about 210 mg / ml per week, about 220 mg / ml per week, about 230 mg / ml per week, about 240 mg / ml per week, about 250 mg / ml per week, about 260 mg / ml per week, about 270 mg / ml per week, about 280 mg / ml per week, about 290 mg / ml per week, about 300 mg / ml per week, about 310 mg / ml per week, about 320 mg / ml per week, about 330 mg / ml per week, about 340 mg / ml per week, about 350 mg / ml per week, about 360 mg / ml per week, about 370 mg / ml per week, about 380 mg / ml per week, about 390 mg / ml per week, about 400 mg / ml per week, about 410 mg / ml per week, about 420 mg / ml per week, about 430 mg / ml per week, about 440 mg / ml per week, about 450 mg / ml per week, about 460 mg / ml per week, about 470 mg / ml per week, about 480 mg / ml per week, about 490 mg / ml per week, about 500 mg / ml per week, about 510 It can be about 250mg / ml, about 260mg / ml per week, about 270mg / ml per week, about 280mg / ml per week, about 290mg / ml per week, 300mg / ml per week, about 310mg / ml per week, about 320mg / ml per week, about 330mg / ml per week, about 340mg / ml per week, about 350mg / ml per week, about 360mg / ml per week, about 370mg / ml per week, about 380mg / ml per week, about 390mg / ml per week, or 400mg / ml per week.

[0074] II.CDK 4 / 6 Inhibitors In some embodiments of the present application, the method of treating cancer comprises co-administering a CDK 4 / 6 inhibitor with gedatolicib to a subject. As used herein, the term "CDK 4 / 6 inhibitor" includes compounds that inhibit CDK4 activity, CDK6 activity, or both CDK4 and CDK6 activity.

[0075] The regulation of the cell cycle is governed and controlled by specific proteins, which are activated and deactivated in a precisely timed manner, primarily through phosphorylation / dephosphorylation processes. Key proteins that coordinate the initiation, progression, and completion of the cell cycle program are the cyclin-dependent kinases (CDKs). Cyclin-dependent kinases belong to the serine-threonine protein kinase family. They are heterodimeric complexes composed of a catalytic kinase subunit and a regulatory cyclin subunit. CDK activity is controlled by association with their corresponding regulatory subunits (cyclins) and CDK inhibitor proteins (Cip and Kip proteins, INK4), by their phosphorylation status, and by ubiquitin-mediated proteolysis.

[0076] There are four CDKs that are significantly involved in cell proliferation: CDK1, which mainly regulates the transition from G2 to M phase, and CDK2, CDK4, and CDK6, which regulate the transition from G1 to S phase. When cells are responsive to mitogenic stimuli in early to mid G1 phase, the activation of CDK4-cyclin D and CDK6-cyclin D induces the phosphorylation of retinoblastoma protein (pRb). The phosphorylation of pRb releases the transcription factor E2F, which enters the nucleus and activates the transcription of other cyclins that promote further progression of the cell cycle. CDK4 and CDK6 are closely related proteins with essentially indistinguishable biochemical properties.

[0077] Several CDK 4 / 6 inhibitors have been identified, including certain pyrido[2,3-d]pyrimidines, 2-anilinopyrimidines, diarylureas, benzoyl-2,4-diaminothiazoles, indolo[6,7-a]pyrrolo[3,4-c]carbazoles, and oxindoles. For example, International Publication No. WO03 / 062236 identifies a series of 2-(pyridin-2-ylamino-pyrido[2,3]pyrimidin-7-ones for the treatment of Rb-positive cancers that exhibit selectivity for CDK4 / 6, including 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido-[2,3-d]-pyrimidin-7-one (PD0332991). Tate et al. describe the antitumor activity of the CDK4 / 6 inhibitor abemaciclib (LY2835219) (“Semi-Mechanistic Pharmacokinetic / Pharmacodynamic Modeling of the Antitumor Activity of LY2835219, a New Cyclin-Dependent Kinase 4 / 6 Inhibitor, in Mice Bearing Human Tumor Xenografts”, Clin Cancer Res (Jul. 15, 2014) 20; 3763). Rader et al. describe the reduction of proliferation in neuroblastoma-derived cell lines using the CDK4 / 6 inhibitor ribociclib (LEE011) (“Dual CDK4 / CDK6 Inhibition Induces Cell Cycle Arrest and Senescence in Neuroblastoma”, Clin Cancer Res (Nov. 15, 2013) 19(22): 6173-82). VanderWel et al. describe iodine-containing pyrido[2,3-d]pyrimidin-7-ones (CKIAs) as potent and selective CDK4 inhibitors (see VanderWel et al., J. Med. Chem. 48 (2005) 2371-2387).International Publication No. WO99 / 15500, filed by Glaxo Group Ltd, discloses protein kinase and serine / threonine kinase inhibitors. International Publication No. WO2010 / 020675, filed by Novartis AG, describes pyrrolopyrimidine compounds as CDK inhibitors. International Publication No. WO2011 / 101409, also filed by Novartis, describes pyrrolopyrimidines with CDK 4 / 6 inhibitory activity. International Publication No. WO2005 / 052147, filed by Novartis, and International Publication No. WO2006 / 074985, filed by Janssen Pharma, disclose further CDK4 inhibitors. International Publication No. WO2012 / 061156, filed by Tavares and assigned to G1 Therapeutics, describes CDK inhibitors. International Publication No. WO2013 / 148748, filed by Francis Tavares and assigned to G1 Therapeutics, describes lactam kinase inhibitors.

[0078] Selective CDK4 / 6 inhibitors are generally designed to target CDK4 / 6 replication-dependent cancers. For example, Michaud et al. reported that the CDK4 / 6 inhibitor PD-0332991 was inactive against Rb-negative tumors (Michaud et al., Pharmacologic Inhibition of Cyclin-Dependent Kinase 4 and 6 Arrests the Growth of Glioblastoma Multiform Intracranial Xenografts. Cancer Res. 70:3228-3238 (2010)).

[0079] In some embodiments, the CDK 4 / 6 inhibitor is selected from the group consisting of palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, ribiciclib, and combinations thereof.

[0080] The CDK 4 / 6 inhibitor may be administered using methods known in the art. In some embodiments, the CDK 4 / 6 inhibitor is palbociclib. Palbociclib (Ibrance™, Pfizer, New York, NY) is available in 125 mg, 100 mg, and 75 mg tablets and capsules. See Ibrance™ prescribing information. The recommended dose of palbociclib is 125 mg taken orally once daily for 21 consecutive days, followed by 7 days off treatment, which constitutes a complete 28-day cycle. Ibid. This treatment cycle may be modified based on the outcome of the treatment and the patient's tolerance. Ibid. For example, if a patient experiences neutropenia, the administration of palbociclib may be reduced to 100 mg or 75 mg once daily for 21 consecutive days, followed by 7 days off treatment. Ibid.

[0081] Ribociclib (Kisqali™, Novartis, Switzerland) is available in 200 mg tablets. See prescribing information for Kisqali™. The recommended dose of ribociclib is 600 mg (three 200 mg tablets) taken orally once daily for 21 consecutive days, followed by 7 days off treatment, which constitutes a complete 28-day cycle. Ibid. This treatment cycle may be modified based on the outcome of treatment and patient tolerance. Ibid. For example, if a patient experiences negative side effects, the administration of ribociclib may be reduced to 400 mg or 200 mg once daily for 21 consecutive days, followed by 7 days off treatment. Ibid.

[0082] Abemaciclib (Verzenio™, Eli Lilly, Indianapolis, IN) is available in 200 mg, 150 mg, 100 mg, and 50 mg tablets. See prescribing information for Verzenio™. The recommended dose of abemaciclib, when administered in combination with fulvestrant, is 150 mg twice daily. Ibid. The recommended dose of abemaciclib, when administered without fulvestrant, is 200 mg twice daily. Ibid. If dose reduction is necessary, it is recommended that the abemaciclib dose be reduced by 50 mg at a time. Ibid.

[0083] Trilaciclib (Cosela™, G1 Therapeutics, Inc., NC) is available as a 300 mg lyophilized powder in single-dose vials. See Cosela™ prescribing information. The recommended dose of trilaciclib is 240 mg / m per dose administered as an intravenous (IV) infusion. 2 Ibid. Trilaciclib should be reconstituted with 19.5 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection USP to obtain a concentration of 15 mg / mL. Ibid. Trilaciclib is generally administered as a 30-minute intravenous infusion, which should be completed within 4 hours prior to the start of chemotherapy on each day chemotherapy is administered. Ibid.

[0084] Darpiciclib (SHR6390, Jiangsu Hengrui Medicine Co.) is in clinical trials, dosed at 150 mg orally once daily on days 1 to 21 of every 28-day cycle, followed by a 7-day treatment break. See NCT04236310, January 17, 2020. Darpiciclib is currently being investigated in combination with letrozole or anastrozole or fulvestrant in patients with HR-positive and HER2-negative advanced breast cancer.

[0085] Ribiciclib (P276-00, Piramal Enterprises Ltd., Mumbai, IN) is in clinical trials and is administered at 185 mg / m2 in 200 ml of 5% dextrose over 30 minutes per day on days 1 to 5 of a 21-day cycle. 2 It has been administered as an intravenous infusion at a concentration of 100 mg / kg / day. See NCT00898287, January 20, 2012. Ribiciclib is being investigated in combination with gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer.

[0086] III. Estrogen Receptor Antagonists Estrogen receptor (ER) is a ligand-activated transcriptional regulatory protein that mediates the induction of various biological actions through interaction with endogenous estrogens.Endogenous estrogens include 17β (beta)-estradiol and estrone.ER has been found to have two isoforms, ER-α (alpha) and ER-β (beta).

[0087] In some embodiments of the present application, the method of treating cancer comprises co-administering to a subject an estrogen receptor antagonist and optionally a CDK 4 / 6 inhibitor together with gedatolicib. As used herein, the term "estrogen receptor antagonist" includes compounds that act competitively by displacing estrogen from the receptor.

[0088] ARN-810 (GDC-0810, Seragon Pharmaceuticals, Genentech Inc.) is a small molecule, nonsteroidal, selective ER modulator that antagonizes the action of estrogen and induces ER degradation via the proteasome. ARN-810 is in clinical trials as an orally delivered therapy for the treatment of advanced metastatic ER-α positive (ER+) breast cancer.

[0089] PCT Publication No. WO2013 / 090836 discloses fluorinated estrogen receptor modulators and uses thereof.

[0090] PCT Publication No. WO2014 / 205136 discloses azetidine estrogen receptor modulators and uses thereof.

[0091] US Patent Application Publication No. 2003 / 0130274 discloses 2-phenyl-1-[4-(2-aminoethoxy)benzyl]-indoles as estrogenic agents.

[0092] One exemplary estrogen receptor antagonist useful in the methods of the present application is fulvestrant.

[0093] Fulvestrant (Faslodex™, AstraZeneca, Cambridge, UK) is available for injection for intramuscular administration supplied as a 250 mg / 5 mL vial. See prescribing information for Faslodex™. The recommended dosing of fulvestrant is 500 mg administered slowly intramuscularly in the buttocks (gluteal area) as two 5 mL injections on days 1, 15, 29, and once a month thereafter. See ibid. For patients with moderate hepatic impairment, the recommended dose is 250 mg administered intramuscularly as one 5 mL injection on days 1, 15, 29, and once a month thereafter. See ibid.

[0094] IV. Formulation In some embodiments, the gedatolisib, CDK 4 / 6 inhibitors, and estrogen receptor antagonists used in the methods of the present application may be formulated with one or more pharma- ceutically acceptable excipients to form a pharmaceutical composition.

[0095] The pharmaceutical compositions used in the methods disclosed herein may be specially formulated in solid or liquid form, including those adapted for parenteral administration, e.g., as sterile solutions or suspensions, e.g., by intravenous, subcutaneous, intratumoral, or intramuscular injection or infusion.

[0096] The injectable or infusion formulation of the pharmaceutical composition used in the method disclosed herein can be prepared by known methods. For example, the injectable or infusion formulation can be prepared by dissolving, suspending, or emulsifying, for example, the FcRn inhibitor or its salt in a sterile aqueous or oily medium that is conventionally used for injection. Aqueous media for injection or infusion include, for example, saline, isotonic solutions containing glucose and other auxiliary agents, which can be used in combination with suitable solubilizers, for example, alcohols (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), non-ionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil), etc.). Oily media used include, for example, sesame oil, soybean oil, etc., which can be used in combination with solubilizers, for example, benzyl benzoate, benzyl alcohol, etc. The injection or infusion preparation thus prepared is preferably filled into an appropriate injection ampule or a vial or bag suitable for injection.

[0097] A pharma- ceutically acceptable excipient can be a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, manufacturing aid (e.g., lubricants, talc, magnesium, calcium, or zinc stearate, or stearic acid), solvent or encapsulating material, involved in carrying or transporting a therapeutic compound for administration to a subject, bulking agents, salts, surfactants, and / or preservatives. Some examples of materials that can function as pharma- ceutically acceptable excipients include sugars such as lactose, glucose, and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate, gelatin, talc, waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, glycols such as ethylene glycol and propylene glycol, polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers, water, isotonic saline, pH buffered solutions, and other non-toxic compatible substances utilized in pharmaceutical formulations.

[0098] Bulking agents are compounds that add mass to a pharmaceutical formulation and contribute to the physical structure of the formulation in lyophilized form. Suitable bulking agents according to the present invention include mannitol, glycine, polyethylene glycol, and sorbitol.

[0099] The use of a surfactant can reduce aggregation of the reconstituted protein and / or reduce the formation of particulates in the reconstituted formulation. The amount of surfactant added is such that it reduces aggregation of the reconstituted protein and minimizes the formation of particulates after reconstitution. Suitable surfactants according to the present invention include polysorbates (e.g., polysorbate 20 or 80), poloxamers (e.g., poloxamer 188), Triton®, sodium dodecyl sulfate (SDS), sodium lauryl sulfate (sodium lauryl sulfate), and the like. sulfate), sodium octyl glycoside, lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine, lauryl-, myristyl-, linoleyl-, or stearyl-sarcosine, linoleyl-, myristyl-, or cetyl-betaine, lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl), myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine, sodium methyl cocoyl-taurate or disodium methyl oleyl-taurate, and polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronics®, PF68, etc.).

[0100] Preservatives may be used in the formulations provided herein.Suitable preservatives for use in the formulations of the present invention include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkylbenzyl-dimethylammonium chlorides, where the alkyl group is a long-chain compound), and benzethonium chloride.Other types of preservatives include aromatic alcohols, such as phenol, butyl and benzyl alcohol, alkyl parabens, such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol.Other suitable excipients can be found in standard pharmaceutical textbooks, such as "Remington's Pharmaceutical Sciences", The Science and Practice of Pharmacy, 19th Ed. Mack Publishing Company, Easton, Pa., (1995).

[0101] In some embodiments, the gedatolisib, and optionally the CDK 4 / 6 inhibitor, and / or estrogen receptor antagonist used in the methods disclosed herein may be lyophilized and provided in a composition for reconstitution prior to administration.

[0102] V. Kits and Unit Dosage Forms Also provided herein is a kit that includes a pharmaceutical composition that contains gedatolicib, and optionally a CDK 4 / 6 inhibitor, and / or an estrogen receptor antagonist, and a pharma- ceutical acceptable carrier in a therapeutically effective amount that is adapted for use in the methods described herein.The kit can also include instructions, including, for example, administration schedules, so that a practitioner (e.g., a doctor, a nurse, or a patient) can administer the composition contained therein to a patient with cancer.The kit can also include a syringe.

[0103] Optionally, the kit includes multiple packages of single-dose pharmaceutical compositions, each containing an effective amount of gedatrisib (e.g., 180 mg) for single administration by the method provided above. The equipment or device required for administration of the pharmaceutical composition may also be included in the kit. For example, the kit may provide one or more pre-filled syringes containing the amount of liquid required for reconstitution of gedatrisib.

[0104] VI. Target Population Subjects treated with the methods described herein may have one or more of the following characteristics:

[0105] In one embodiment, the subject needs to treat cancer. In some embodiments, the cancer is a solid cancer (i.e., solid tumor). The solid cancer can be selected from the group consisting of breast cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, prostate cancer, testicular cancer, penile cancer, lung cancer, colorectal cancer, melanoma, bladder cancer, brain / CNS cancer, esophageal cancer, gastric cancer, head / neck cancer, kidney cancer, liver cancer, pancreatic cancer, and sarcoma.

[0106] Cancers that can be treated with the methods and compositions described herein include, but are not limited to, solid cancers that are hormone-dependent, hormone-responsive, and / or hormone-sensitive (collectively, "hormone-responsive cancers"). Exemplary cancers that can be treated include, without limitation, androgen-responsive cancers, such as estrogen-responsive cancers and testosterone-responsive cancers. In some embodiments, the cancer may be a non-hormone-responsive cancer, where a cancer that previously responded to hormone treatment has subsequently become non-hormone-responsive. Exemplary hormone-dependent cancers include, but are not limited to, breast cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, prostate cancer, testicular cancer, and penile cancer. In some embodiments, the hormone-dependent cancer is breast cancer.

[0107] In some embodiments, the subject of the method herein is in need of breast cancer treatment.Breast cancer can be diagnosed using any method known in the art.For example, cancer can be diagnosed through testing of the subject's tumor (e.g., tumor biopsy), blood, body fluids, or other tissues.Subjects can also undergo biomarker testing to determine the classification of breast cancer.

[0108] The term "biomarker" in its most general sense refers to a biological metric of a state related to the health or disease status of a cell or a patient. A non-limiting list of common biomarkers includes biologically derived molecules found in mammals, biological activity of mammalian cells or tissues, gene copy number, gene mutations, single nucleotide polymorphisms, gene expression levels, mRNA levels, splice variants, transcriptional modifications, post-transcriptional modifications, epigenetic modifications, cell surface markers, differential expression of proteins or nucleic acids (including all forms of functional RNA), amplification of nucleic acids, cell morphology, post-translational modifications, protein cleavage, phosphorylation, dephosphorylation, ubiquitination, deubiquitination, metabolites, hormones at any stage of biosynthesis, cytokines, chemokines, and combinations thereof. A subset of biomarkers is used for diagnostic and treatment selection purposes to assist pathologists in diagnosing disease and physicians in prescribing treatment. Biomarkers typically measure gene copy number, gene mutations, or protein levels without specification of protein status or activity in fixed and mounted tissues.

[0109] The term "biomarker status" refers to the assessment of a biomarker in a patient or in a patient's cells, typically reported as "biomarker positive" if the biomarker is present, or "biomarker negative" if the biomarker is absent. When protein receptors are used as biomarkers (e.g., HER2 / ErbB2 or ER), a biomarker positive result also refers to the receptor being overexpressed or amplified, and a biomarker negative result refers to the receptor being normally expressed or not amplified. For diseases in which biomarkers or biomarker signatures are prognostic indicators of disease progression or they predict treatment efficacy, current clinical practice refines patient diagnosis by classifying patients as either biomarker negative or positive, depending on the measurement of the amount of the biomarker or its associated mutations.

[0110] The term "HER2 / ErbB2 status" refers to the evaluation of the expression of HER2 / ErbB2 in a patient or in a patient's cells (e.g., cancer cells) as a biomarker, typically reported as "HER2 / ErbB2 positive" if the biomarker is present in excess compared to normal healthy non-cancerous breast tissue samples, or "HER2 / ErbB2 negative" if the biomarker is present at levels not exceeding normal healthy non-cancerous breast tissue samples, as determined by IHC staining tests of fixed tissue samples. Various methods are known in the art for evaluating HER2 / ErbB2 status, typically focusing on the amount of receptor expressed by the patient's cells (IHC), or mRNA levels (qPCR), or gene copy number (FISH), thereby diagnosing a patient as HER2 / ErbB positive (if the receptor is overexpressed or amplified in the patient's cells) or HER2 / ErbB negative (if the receptor is neither overexpressed nor amplified in the patient's cells). Overexpression and amplification are terms of art that describe levels that are elevated above those found in similar tissues from normal, disease-free individuals.

[0111] The term "estrogen receptor status" or "ER status" refers to the evaluation of the expression of ER as a biomarker in a patient or in a patient's cells (e.g., cancer cells), and this status is typically reported as "ER positive" if the biomarker is overexpressed in the nucleus of a stained and fixed specimen, or as "ER negative" if the biomarker is normally expressed or absent in the nucleus of a stained and fixed specimen.Various methods are known in the art for evaluating ER status, typically focusing on the amount of receptor expressed by the patient's cells (IHC) or mRNA levels (qPCR), thereby diagnosing a patient as ER positive (if the receptor is expressed in the patient's cells) or ER negative (if the receptor is not expressed in the patient's cells).

[0112] The terms "targeted pathway drug," "pathway drug," or "targeted drug" refer to any molecule or antibody with therapeutic potential that is designed to bind to a specific biomolecule (e.g., a protein) involved in a disease process, thereby modulating its activity.

[0113] The term "HER2 therapy" or "HER2 targeted therapy" refers to treatment with one or more therapeutic agents designed to specifically target the HER2 molecule and / or signaling pathway, including, but not limited to, antibodies and small molecules that target the HER2 molecule and / or signaling pathway. Such HER2 therapy may also target other members of the HER family, for example, therapy that targets both HER1 and HER2, HER1, HER2, and HER4, or HER3 alone.

[0114] The terms "ER therapy," "ER-targeted therapy," or "hormonal therapy" refer to treatment with one or more therapeutic agents designed to specifically target the ER molecule and / or signaling pathway, including, but not limited to, aromatase inhibitors, selective estrogen receptor modulators, and selective estrogen receptor degraders, as well as combinations of such therapies with therapies that inhibit the cyclin-dependent kinases CDK4 and CDK6.

[0115] In some embodiments, the breast cancer is metastatic, hormone resistant, estrogen receptor positive, estrogen receptor negative, progesterone receptor negative, progesterone receptor positive, triple negative, HER2 positive, or HER2 negative breast cancer.In further embodiments, the subject is a premenopausal or postmenopausal female patient.

[0116] In some embodiments, breast cancer is of basal or luminal subtype. Breast cancer is known to be a heterogeneous disease. There are different subtypes that can be defined based on (i) molecular profile of breast cancer tumors, (ii) gene array testing, or (iii) immunohistochemical analysis approach. Specifically, breast ducts are bilayer structures composed of luminal and myoepithelial layers attached to a basement membrane. The term basal refers to certain cancers that arise from the basal layer of stratified epithelium. Breast cancer of basal subtype resides in the basal layer opposite to the apical or luminal layer of ductal epithelium of the breast. Such cancers have distinct and distinct cytological characteristics and gene expression profiles, for example, intermediate fiber profile (cytokeratin) that is first observed in basal cells of skin.

[0117] Approximately 14-20% of breast cancers are basal-like. Basal-like breast cancers are triple-negative ER- / PR- / HER2- with respect to immunophenotypic markers, but differ from luminal cancers in that they express CK5 / 6. Basal-like breast cancers exhibit increased hypoxia and high tumor grade, and have an invasive phenotype characterized by high cell proliferation and poor clinical outcomes. Most BRCA1 and many BRCA2 breast cancers are both triple-negative / basal-like. Triple-negative / basal-like tumors are invasive and often have a poorer prognosis compared to estrogen receptor-positive subtypes (luminal A and luminal B tumors). Triple-negative / basal-like tumors are usually treated with some combination of surgery, radiation therapy, and chemotherapy. These tumors are hormone receptor-negative and HER2 / neu-negative, and therefore cannot be treated with hormone therapy or trastuzumab.

[0118] Most breast cancers are luminal tumors. Luminal tumor cells resemble breast cancer cells that originate from the internal (luminal) cells lining the milk ducts. Luminal A breast cancers are ER+ and / or PR+, HER2-, and have low Ki67. Approximately 42-59% of breast cancers are luminal A. Luminal A tumors tend to be of low or intermediate tumor grade. Of the four subtypes, luminal A tumors tend to have the best prognosis, with very high survival rates and very low recurrence rates. Only about 15% of luminal A tumors have p53 mutations, a factor linked to a poorer prognosis.

[0119] Luminal B breast cancers are ER+ and / or PR+, HER2+ (or HER2- with high Ki67). Approximately 6-17% of breast cancers are luminal B. Women with luminal B tumors are more likely to be diagnosed at a younger age than those with luminal A tumors. Compared to luminal A tumors, luminal B tumors also tend to have factors that result in a poorer prognosis, including poorer tumor grade, larger tumor size, and p53 gene mutations. In general, women with luminal B tumors have a very high survival rate, although not as high as those with luminal A tumors.

[0120] In some embodiments, the breast cancer is ductal carcinoma in situ (carcinoma in a breast duct), lobular carcinoma in situ, invasive (or infiltrating) ductal carcinoma, invasive (or infiltrating) lobular carcinoma, inflammatory breast cancer, triple-negative breast cancer, Paget's disease of the nipple, phyllodes tumor, angiosarcoma, or invasive breast cancer. In some embodiments, invasive breast cancer is further categorized into subtypes. In some embodiments, the subtypes include adenoid cystic (or adenocystic) carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous (or colloidal) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, or mixed carcinoma.

[0121] In some embodiments, breast cancer is classified according to stage, or how far tumor cells have spread within breast tissue and to other parts of the body. There are five stages of breast cancer: stage 0 to stage IV. The methods of treating cancer described herein can be used to treat patients with breast cancer classified as stage 0 to stage IV.

[0122] Stage 0 breast cancer refers to non-invasive breast cancer or cancer with no evidence of cancer cells or abnormal non-cancerous cells leaving the site of origin. Stage I breast cancer refers to invasive breast cancer where cancer cells have invaded surrounding tissues. Stage I is subdivided into stages IA and IB, with stage IA describing a tumor measuring up to 2cm and no spread of cancer cells. Stage IB describes no tumor in the breast but small lumps of cancer cells measuring 0.2mm to 2mm in the lymph nodes. Stage II breast cancer is further subdivided into stages IIA and IIB. Stage IIA describes a tumor measuring 2cm to 5cm in the breast only, or no tumor in the breast but cancer measuring 2mm to 2cm in the axillary lymph nodes. Stage IIB describes a tumor larger than 5cm in the breast only, or a tumor measuring 2cm to 5cm in the breast and small tumors measuring 0.2mm to 2mm in the axillary lymph nodes. Stage III breast cancer is further subdivided into stages IIIA, IIIB, and IIIC. Stage IIIA describes no tumor in the breast or a tumor larger than 5 cm and small tumors in 4-9 axillary lymph nodes or small tumors in the axillary lymph nodes measuring 0.2 mm to 2 mm in size. Stage IIIB describes tumors that have spread to the chest wall or skin of the breast causing swelling or ulceration and tumors in up to 9 axillary lymph nodes. Inflammatory breast cancer is also considered stage IIIB. Stage IIIC describes no tumor or tumors that have spread to the chest wall or skin of the breast and tumors in 10 or more axillary lymph nodes. Stage IV breast cancer refers to invasive breast cancer that has spread to lymph nodes and other parts of the body.

[0123] In other embodiments, the cancer may be adrenal gland cancer, lymphatic system, e.g., cancer of the lymph nodes, leukemia, lymphoma, myeloma, Waldenstrom's macroglobulinemia, monoclonal gammopathy, benign monoclonal gammopathy, heavy chain disease, sarcoma of bone and connective tissue, brain tumor, thyroid cancer, pancreatic cancer, pituitary cancer, eye cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, bile duct cancer, lung cancer, oral cancer, skin cancer, kidney cancer, Wilms' tumor, and bladder cancer.

[0124] In some embodiments, the human subject has failed a prior treatment (e.g., an endocrine treatment) for cancer (e.g., breast cancer) for less than 12 months (e.g., less than 6 months). In some embodiments, the human subject has failed two or more prior treatments for cancer. The failed prior treatments can be endocrine and / or non-endocrine treatments for cancer.

[0125] VII. Administration Administration of gedatolisib in a 28-day cycle (weekly administration for three weeks with one week of gedatolisib off) has been found to be more effective when compared to a non-periodic (weekly) administration schedule. The 28-day cycle involves administering gedatolisib intravenously once a week for three weeks (e.g., on days 1, 8, and 15 of the cycle), followed by one week without gedatolisib (e.g., no gedatolisib on day 21).

[0126] One aspect of the present invention relates to a method for treating cancer in a human subject. The method includes the step of selecting a human subject in need of cancer treatment. The human subject is administered a therapeutically effective amount of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, at least once a week for a period of three weeks. This is followed by one week during which administration of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof is discontinued. Administration of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, is then resumed at least once a week after the discontinuation period. The administration for a period of at least three weeks and the administration interruption for a period of at least one week constitute one cycle, and this cycle is repeated for at least two cycles.

[0127] In some embodiments, the resumed administration of gedatricisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, occurs at least once a week for a period of three weeks.

[0128] In further embodiments, the cycle of administration occurs for at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles, at least 9 cycles, or at least 10 cycles, or more. Administration can occur as many cycles as necessary to obtain a desired outcome (e.g., remission of cancer), or until treatment is no longer required. For example, administration can occur for at least 20 cycles, at least 30 cycles, at least 40 cycles, or at least 50 cycles.

[0129] In some embodiments, gedatrisib or its pharmaceutically acceptable salt, solvate or ester is administered at a dose of 180mg once a week.As will be clear to those skilled in the art, the dose of gedatrisib administered to a subject can be increased or decreased depending on the subject, the severity of disease and the mode of administration.For example, the dose of gedatrisib administered can range from about 25mg per week, 50mg per week, 100mg per week, 150mg per week or 200mg per week, up to about 50mg per week, 100mg per week, 150mg per week, 225mg per week or 250mg per week.

[0130] The methods described herein may also include administration of an additional therapeutic compound. The additional therapeutic compound may be administered simultaneously with gedatolisib. Alternatively, administration of the additional therapeutic compound may occur non-concurrently with administration of gedatolisib.

[0131] In some embodiments, the method also includes administering to the human subject a CDK 4 / 6 inhibitor at least once a week for a period of 3 weeks. The administration of the CDK 4 / 6 inhibitor is then discontinued for a period of 1 week, followed by a resumed administration of the CDK 4 / 6 inhibitor for at least 1 week. The cycle of administration and discontinuation of the CDK 4 / 6 inhibitor is repeated for at least 2 cycles.

[0132] In some embodiments of the method of treating cancer, the administration of CDK 4 / 6 inhibitor occurs during the same week as the administration of gedatolicib, or its pharma- ceutically acceptable salt, solvate, or ester. The CDK 4 / 6 inhibitor that may be useful in the method herein includes, but is not limited to, palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, ribiciclib, and combinations thereof. Preferably, the CDK 4 / 6 inhibitor is palbociclib. Palbociclib can be administered at a dose that produces the desired outcome as determined by a physician. For example, the dose of palbociclib can be 125 mg per day, 100 mg per day, or 75 mg per day. Preferably, the dose of palbociclib is 125 mg per day.

[0133] Some embodiments of the method of treating cancer include administering an estrogen receptor antagonist to a human subject. Examples of estrogen receptor antagonists that can be used in the method of the present invention are discussed above. Preferably, the estrogen receptor antagonist is fulvestrant. Fulvestrant can be administered at a dose that produces the desired outcome as determined by a physician. For example, the dose of fulvestrant can be 500mg or 200mg, as an intramuscular injection, every other week (e.g., on days 1, 15, and 29) for six weeks, and once a month thereafter. In some embodiments, fulvestrant is administered at a dose of 500mg every two weeks. In a further embodiment, fulvestrant is administered at a dose of 500mg every four weeks.

[0134] A further aspect of the present application relates to a method for treating cancer in a human subject, comprising the step of selecting a human subject in need of cancer treatment. The method comprises administering to the human subject a therapeutically effective amount of gedatrisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor at least once a week for a period of three weeks. This is followed by a one-week period during which administration of gedatrisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor is suspended. Administration of gedatrisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor is then resumed at least once a week after the suspension period. Administration for a period of at least three weeks and administration suspension for a period of at least one week constitute one cycle, and this cycle is repeated at least two cycles.

[0135] In some embodiments, the resumed administration of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, and the CDK 4 / 6 inhibitor occurs at least once a week for a period of three weeks.

[0136] Another aspect of the present application relates to a method for treating cancer in a human subject, the method comprising the steps of: selecting a human subject in need of cancer treatment; administering to the human subject a therapeutically effective amount of gedatrisib, or a pharma- ceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor at least once a week for a period of three weeks; discontinuing administration of gedatrisib, or a pharma-ceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor for a period of one week; and resuming administration of gedatrisib, or a pharma-ceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor at least once a week after the discontinuance period, wherein the administration for a period of at least three weeks and the administration discontinuance for a period of at least one week constitute one cycle, and the cycle is repeated for at least two cycles; and administering to the human subject an estrogen receptor antagonist.

[0137] In some embodiments, a human subject is administered gedatolisib intravenously once a week for three weeks, followed by one week without gedatolisib, for the treatment of hormone-dependent cancer (e.g., breast cancer). In some embodiments, the subject has failed a prior treatment (e.g., endocrine treatment) for breast cancer in less than 12 months (e.g., 6 months). In some embodiments, the subject has failed two or more prior treatments for cancer. The failed prior treatments can be endocrine and / or non-endocrine treatments for cancer or cancer.

[0138] The method of the present invention can be used as adjuvant treatment.As used herein, "adjuvant treatment" refers to the treatment of cancer patients immediately after the first non-chemotherapeutic treatment, such as surgery or radiation therapy.In general, the purpose of adjuvant therapy is to provide a significantly lower risk of recurrence compared to the case without adjuvant therapy.For example, the subject can undergo surgery or radiation therapy, and then undergo treatment using the method described herein.

[0139] The outcome and effectiveness of the methods described herein can be evaluated using any suitable method.Cancer symptoms that can be attenuated or eliminated by the methods disclosed herein include, but are not limited to, any subjective, objective, or quantitative evidence of disease or other physical abnormalities in subjects or patients.For example, symptoms can include tumor size, pain, headache, nausea, blood markers that indicate cancer or cancer progression (e.g., CA15.3, TRU-QUANT, CA27.29, CA125, CEA (carcinoembryonic antigen), circulating tumor cells), etc.

[0140] In some embodiments, the methods of treatment result in prolonged progression-free survival (PFS), overall survival (OS), and improved quality of life.

[0141] In some embodiments, the subject achieves partial response (PR).Partial response can be defined as a reduction in tumor size without achieving complete remission.The reduction in tumor size can allow the subject to undergo surgery to remove the tumor.

[0142] In some embodiments, the subject achieves a complete response (CR), which may be defined as the complete remission of the cancer.

[0143] VIII. Additional Combination Therapies In some embodiments, the present invention provides a method of treating cancer, comprising administering to a subject gedatolisib (e.g., according to a dosage regimen described herein) in combination or in a combination treatment regimen with one or more additional anti-cancer agents. In an embodiment, the anti-cancer agent is a checkpoint inhibitor. In an embodiment, the checkpoint inhibitor is a biotherapeutic agent or a small molecule. The checkpoint inhibitor can be a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. The checkpoint inhibitor can inhibit a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligand, and a combination thereof. A checkpoint inhibitor may interact with a ligand of a checkpoint protein, which may be CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, or a combination thereof. In some embodiments, the therapeutic agent is an immune stimulant, a T cell growth factor, an interleukin (e.g., IL-7 or IL-15), an antibody, a vaccine (e.g., a dendritic cell (DC) vaccine), or a combination thereof.

[0144] In some embodiments, the efficacy of treatment is determined by a clinical outcome, such as an increase, enhancement, or prolongation of anti-tumor activity by T cells, an increase in the number of anti-tumor T cells or activated T cells compared to the number before treatment, or a combination thereof. In another aspect, the clinical outcome is tumor stabilization, tumor regression or stabilization, tumor reduction, tumor necrosis, an anti-tumor response by the immune system, inhibition of tumor growth, recurrence, or spread, or a combination thereof.

[0145] In further embodiments, the checkpoint inhibitor and gedatolisib are administered simultaneously or sequentially in either order, hi additional embodiments, gedatolisib is administered prior to the checkpoint inhibitor.

[0146] In certain embodiments, the additional anti-cancer agent that may be co-administered to the subject is a chemotherapeutic agent, for example a cytotoxic chemotherapeutic pharmaceutical compound.

[0147] As used herein, the term "chemotherapy" or "chemotherapeutic agent" refers to treatment with cytostatic or cytotoxic agents (i.e., compounds) to reduce or eliminate the growth or proliferation of unwanted cells, e.g., cancer cells. Thus, as used herein, "chemotherapy" or "chemotherapeutic agent" refers to cytotoxic or cytostatic agents used to treat proliferative disorders, e.g., cancer.

[0148] Exemplary cytotoxic chemotherapeutic pharmaceutical compounds include, but are not limited to, cyclophosphamide, ifosamide, methotrexate, substituted nucleotides, substituted nucleosides, fluorouracil, mitomycin, adriamycin, vincristine, vindesine, taxol, cisplatin, carboplatin, etoposide, or combinations thereof.

[0149] In some embodiments, in addition to gedatolisib, the subject is administered adjunctive therapy, such as an analgesic for headache, treatment for infusion-related reaction (IRR), and prophylaxis for infusion-related reaction. Symptoms of IRR include, for example, flushing, changes in heart rate and blood pressure, dyspnea, bronchospasm, back pain, fever, urticaria, edema, nausea, and rash.

[0150] In some embodiments, the treatment for IRR is selected from the group consisting of acetaminophen, IV hydration, diphenhydramine, histamine 2 blockers (eg, famotidine), and corticosteroids.

[0151] In some embodiments, prophylaxis against an IRR (e.g., if the subject experiences an IRR that requires treatment with a corticosteroid) includes administering hydrocortisone (e.g., hydrocortisone IV) prior to administration of gedatrisib.

[0152] The contents of all figures and all references, Genbank sequences, literature publications, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference in their entirety. Furthermore, if a definition or use of a term in a reference incorporated herein by reference is inconsistent with or contrary to the definition of that term provided herein, the definition of that term provided herein shall apply and the definition of that term in the reference shall not apply.

[0153] The following examples are illustrative only and are not to be construed as limiting the scope of the disclosure in any way, since numerous variations and equivalents will be apparent to those of skill in the art upon reading this disclosure. EXAMPLES

[0154] Example 1: A three-arm Phase 1b study of gedatricisib + palbociclib + fulvestrant in women with metastatic or locally advanced / recurrent breast cancer. Upregulation of the PI3K / AKT / mTOR pathway promotes hormone-dependent and -independent ER transcriptional activity, which contributes to endocrine resistance and results in tumor cell growth, survival, motility, and metabolism. It has also been demonstrated in vivo that PI3K and mTOR inhibition can restore sensitivity to endocrine therapy, providing a strong rationale for the combination of the two therapies. In addition, the PI3K / AKT / mTOR pathway, comparable to other mitogenic pathways, can also promote the activity of cyclin D and CDK4 / 6 to drive the proliferative cell cycle. Internal preclinical studies conducted by Pfizer provided evidence that the combination of PI3K and CDK4 / 6 inhibitors can overcome both intrinsic and adaptive resistance to endocrine therapy and result in tumor regression in cell line xenograft models. In MCF7 xenograft models (ER+ / HER2- / PIK3CA mutant), the combination of gedatolicib with palbociclib and fulvestrant resulted in long-term tumor regression. Importantly, tumors regressed to minimal volume within 20 days of triple therapy and remained dormant without further treatment for up to 90 days.

[0155] To evaluate this hypothesis, Pfizer has initiated a Phase 1b dose-finding study with a four-arm expansion portion to evaluate gedatolicib when added to either standard doses of palbociclib plus letrozole or palbociclib plus fulvestrant for safety and efficacy in patients with ER+ / HER2- metastatic breast cancer. PI3K mutation status was not used as an eligibility criterion. Patient enrollment in this study is complete. A preliminary analysis of 103 patients enrolled in the expansion portion of the Phase 1b clinical trial showed that as of the database cutoff date of January 11, 2021: · 60% objective response rate (ORR): 53 of 88 evaluable patients had either a confirmed or unconfirmed partial response, or PR (48 confirmed, 5 unconfirmed). · 75% Clinical Benefit Rate (CBR): 66 of 88 evaluable patients had either a confirmed PR or stable disease for 24 weeks. Patients enrolled in Arm D represent the study population enrolled in this trial, patients whose most recent prior treatment was endocrine therapy in combination with a CDK4 / 6 inhibitor. Median progression-free survival was 13.2 months. This equates to a weighted average median PFS for standard of care treatment of approximately 5.7 months.

[0156] 1. Purpose The primary objective of this study was to evaluate the safety, tolerability, and maximum tolerated dose (MTD) of the triple combination of gedatolicib added to standard doses of either palbociclib / letrozole or palbociclib / fulvestrant.Another objective was to determine whether the triple combination of gedatolicib + palbociclib / letrozole or gedatolicib + palbociclib / fulvestrant produces superior objective responses (ORs) in patients with metastatic breast cancer (mBC) compared with historical control data on the two-drug combination of palbociclib plus either letrozole or fulvestrant.

[0157] Secondary objectives included further evaluation of the safety and tolerability of the combinations tested in this study to evaluate antitumor activity in the dose escalation portion, to evaluate additional efficacy parameters including duration of response (DR) and progression-free survival (PFS) in the expansion portion, to characterize the potential for QTc interval prolongation, to evaluate single and multiple dose pharmacokinetics (PK) of gedatolicib and palbociclib, and multiple dose pharmacokinetics of fulvestrant and letrozole (dose escalation portion only), and to evaluate single and multiple dose pharmacokinetics (PK) of gedatolicib (dose expansion portion only).

[0158] 2.Research design This is a phase 1b multicenter, open-label study in patients with mBC. The study has both dose escalation and expansion parts. The dose escalation part will identify the MTD of the combinations of gedatricisib + palbociclib / letrozole and gedatricisib + palbociclib / fulvestrant. The expansion part will estimate the objective response rates of the combinations of gedatricisib + palbociclib / letrozole and gedatricisib + palbociclib / fulvestrant.

[0159] The dose escalation and dose expansion study populations consisted of patients of any menopausal status with ER-positive, HER2-negative, metastatic, or locally recurrent / advanced breast cancer (mBC).

[0160] The dose escalation portion of the study will first evaluate the safety and tolerability of gedatolicib at a dose of 180 mg / week plus standard dose palbociclib / letrozole, or gedatolicib at a dose of 180 mg / week plus standard dose palbociclib / fulvestrant. The dose escalation portion will then explore gedatolicib plus dose escalation of each regimen. During dose escalation, 10 DLT-evaluable patients will be treated at the predicted MTD.

[0161] Once the MTD of each combination has been determined, this will trigger the initiation of an expansion portion that will include the following four arms: (1) Arm A: first-line endocrine-based therapy; (2) Arm B: second- or third-line endocrine-based therapy, no prior palbociclib (or other CDK inhibitor) therapy; (3) Arm C: second- or third-line endocrine-based therapy, with exposure to prior palbociclib (or other CDK inhibitor) therapy, and gedatolicib administered once weekly for 4 weeks; and (4) Arm D: second- or third-line endocrine-based therapy, progression on palbociclib (or other CDK inhibitor) therapy (as most recent regimen), and gedatolicib administered on a 3 weeks on / 1 week off (3:1) schedule.

[0162] All cycles are 28 days in length. Gedatolisib is administered intravenously weekly on days 1, 8, 15, and 22 of each cycle (except for arm D, where gedatolisib is administered on days 1, 8, and 15 of each cycle), palbociclib is administered at 125 mg / day oral continuous dosing for 3 weeks, followed by a week off and repeating each subsequent cycle. Letrozole 2.5 mg daily is administered orally continuously (daily), and fulvestrant is administered intramuscularly at a dose of 500 mg on day 1 of cycle 1, day 15 of cycle 1, day 1 of cycle 2, then day 28 of each subsequent cycle (± 3 days).

[0163] Treatment continued until disease progression, uncontrollable toxicity, patient or investigator decision to discontinue treatment, or end of study. Patients experiencing toxicity, including DLTs, will be managed by dose modification or treatment interruption.

[0164] 3. Study Procedure Safety laboratory tests (hematology, blood chemistry, urinalysis, coagulation) and tumor assessments were performed up to 72 hours prior to the scheduled Day 1 visit in any cycle to facilitate availability of results to the investigator at the time of the clinic visit.

[0165] Other tests and / or increased frequency of laboratory or clinical follow-up may be required in the management of the patient depending on findings from the studies. The results of these additional tests or examinations will be recorded on the Case Report Form (CRF).

[0166] Patients will be assigned an individual study identification number once approved and enrolled.

[0167] Screening evaluations must occur within 28 days (unless otherwise specified) prior to initiation of investigational product. A baseline tumor biopsy specimen may be for archival purposes, and if the patient consents to a new tumor biopsy, this must occur within 28 days prior to initiation of investigational product.

[0168] As part of the screening / baseline evaluation, all patients will undergo a complete medical history including ongoing concomitant medications, clinical evaluation (including physical examination, vital signs, height, weight, ECOG performance status, baseline signs and symptoms, triplicate 12-lead resting electrocardiogram [ECG]), and tumor evaluation. Required baseline laboratory tests include hematology, coagulation and chemistry, HbA1c, pregnancy test, and urinalysis.

[0169] Tumor phenotype and genotype documentation includes histological or cytological classification, stage information, tumor grade, histological subtype, ER / progesterone receptor status, HER2 status, and any known tumor-specific molecular markers. Information on the method used for the initial diagnostic biopsy (biopsy site, biopsy date, type of biopsy) is provided. Genomic methods used to ascertain mutation status are provided. Information on prior antitumor treatment, best response, and duration of treatment is provided for all patients.

[0170] All patients enrolled in the study were asked to provide consent for access to archived tumor biopsies and for testing for genetic variations in proteins and genes associated with various cell signaling pathways, including (but not limited to) components of PI3K and other signaling pathways, such as PTEN, PIK3CA, PIK3R1, and AKT.

[0171] If an archived biopsy was not available at baseline, a new tumor biopsy was required prior to study entry. After completion of screening evaluations and confirmation of eligibility, patients may be enrolled.

[0172] Participants received treatment according to their assigned study arm, and treatment continued until disease progression or unacceptable toxicity.

[0173] 4. Administration of study medication Administration of the study product was performed by an appropriately qualified, Good Clinical Practice (GCP) trained, vaccine-experienced member of the study staff (e.g., physician, nurse, physician assistant, medical professional, pharmacist, or medical assistant) as acceptable by local, state, and institutional guidance.

[0174] Gedatolisib Administration Gedatolisib was administered weekly as an intravenous infusion over approximately 30 minutes (dose escalation; dose expansion: Arm A, Arm B, and Arm C).

[0175] In arm D of the dose expansion portion, gedatolisib was administered as an intravenous infusion over approximately 30 minutes on a 3-week on / 1-week off schedule. No premedication was required.

[0176] Palbociclib Administration Patients were instructed to swallow the palbociclib capsule whole, without manipulating or chewing before swallowing. Broken, cracked, or otherwise not intact capsules should not be ingested. Patients were encouraged to take their dose at approximately the same time each day. Patients were instructed to record daily dosing in a patient diary and to take palbociclib with food. Palbociclib was administered orally once daily for 21 days during each 28-day cycle, followed by 7 days off treatment.

[0177] Letrozole administration The recommended dose of letrozole is one 2.5 mg tablet administered once daily, with or without food.

[0178] Fulvestrant administration Fulvestrant requires a loading dose during the first month of treatment. Fulvestrant doses (500 mg) are administered on days 1, 15, and 1 of cycle 2 (to accommodate the PK schedule). Thereafter, monthly doses are administered on day 28 (± 3 days) of subsequent cycles.

[0179] Fulvestrant injections are given as intramuscular (IM) injections. The 500 mg dose is given as two injections of 250 mg, 5 mL each, administered slowly (over 1 to 2 minutes per injection) into each buttock.

[0180] 5.Endpoints The coprimary efficacy endpoints of this study were (1) first cycle dose-limiting toxicity (DLT) and (2) investigator-assessed objective response (OR).

[0181] Secondary efficacy endpoints of the study were:

[0182] 1) Safety, including adverse events characterized by type, frequency, severity, timing, seriousness, and relationship to study treatment, and laboratory abnormalities characterized by type, frequency, severity, and timing.

[0183] 2) Tumor response on the dose escalation portion of the study.

[0184] 3) DR and PFS (assessed using RECIST v 1.1) for the expansion portion of the study.

[0185] 4) QTc interval.

[0186] 5) Single and multiple dose PK parameters of gedatricisib and palbociclib. Multiple dose PK parameters of fulvestrant and letrozole (dose escalation portion only).

[0187] 6) PK parameters of single and multiple doses of gedatolicib (dose expansion portion only).

[0188] 7.Results Arm D patients received gedatolicib (180 mg IV 3 weeks on / 1 week off). Analysis of the data found that synchronizing the gedatolicib treatment schedule with the palbociclib 3 weeks on / 1 week off schedule was more effective in patients who had failed to receive significant benefit from prior endocrine therapy. This was determined by analyzing the objective response rate and duration of treatment between patients who received gedatolicib on a weekly schedule (arm C) and those who received gedatolicib on a 3 weeks on / 1 week off schedule (arm D) who had failed prior endocrine therapy for less than 12 months. A subset of this patient population (subjects who had failed prior therapy for less than 6 months) was also analyzed. Twenty patients in arm C and 11 patients in arm D had progressed within 12 months of their most recent prior therapy. The median duration of treatment with the most recent prior therapy for these patients was essentially the same (146 days vs. 155 days). Of these patients, 15% in arm C and 73% in arm D reported partial objective responses. The median duration of treatment with gedatricib, palbociclib, and fulvestrant for patients in arm C was 131 days, while the median duration of treatment for patients in arm D was 276 days, more than twice as long as in arm C. The median duration of treatment with gedatricib compared to the most recent prior therapy was 0.9 times longer in arm C and 1.8 times longer in arm D. Twelve patients in arm C and seven patients in arm D had progressed within 6 months of their most recent prior therapy. The median duration of treatment with the most recent prior therapy for these patients was essentially the same (97 days vs. 106 days). Of these patients, 0% in arm C and 71% in arm D reported partial objective responses. The median duration of treatment with gedatolisib, palbociclib, and fulvestrant for patients in arm C was only 81 days, while the median duration of treatment for patients in arm D was 270 days, more than three times longer than in arm C. The median duration of treatment with gedatolisib compared with the most recent preceding therapy was only 0.8 times longer in arm C and 2.6 times longer in arm D. The results are summarized in Table 1. [Table 1]

[0189] As can be seen from the data presented in Table 1, there is an advantage to receiving gedatolisib on a cyclic dosing schedule of 3 weeks on and 1 week off for subjects who have failed previous treatment for less than 12 months (e.g., less than 6 months) (Arm D). When compared with weekly administration of gedatolisib (Arm C), the Arm D group reported higher partial objective responses and had a median duration of treatment that was twice that of the Arm C group.

[0190] The benefit of the 3-week on, 1-week off cyclic dosing schedule of gedatolisib was also seen in patients who had failed two or more prior lines of treatment for their cancer. Patients in arm D were 2.4 times more likely to achieve an objective response (30% or greater reduction in tumor burden) and experience 2.28 times longer periods without tumor progression (progression-free survival) than patients in arm C. The results of the analysis of this patient population are summarized in Table 2. [Table 2]

[0191] The traditional approach to determine the dosing schedule of a cancer patient's treatment regimen is to determine the maximum tolerated dose in a Phase 1 clinical trial. This approach is based on the rationale that the efficacy of a cancer therapeutic drug is directly correlated with the amount of drug administered. The reduction in the dose of a therapeutic drug administered is therefore typically motivated by the need to improve the patient's tolerance of the drug. In this example, however, gedatolisib unexpectedly showed good efficacy when the dosage administered is lower than the maximum tolerated dose (180 mg weekly).

[0192] Those skilled in the art will appreciate that numerous and varied modifications can be made without departing from the scope and spirit of the present disclosure. It is therefore understood that the various embodiments of the present invention described herein are illustrative only and are not intended to limit the scope of the present invention. All references cited herein are incorporated herein by reference in their entirety.

Claims

A composition for use in a method of treating cancer in a human subject, comprising gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein the method comprises: selecting a human subject in need of treatment for cancer; administering to the human subject a therapeutically effective amount of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, at least once a week for a period of three weeks; interrupting the administration of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, for a period of one week; resuming the administration of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, at least once a week after the interruption period; comprising; wherein the administration for at least three weeks and the interruption of administration for at least one week constitute one cycle, and the cycle is repeated at least two cycles, a composition. **Claim 2** The composition according to claim 1, wherein the resumed administration of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, occurs at least once a week for a period of three weeks. **Claim 3** The composition according to claim 1 or 2, wherein at least three cycles, at least four cycles, at least five cycles, at least six cycles, at least seven cycles, at least eight cycles, or at least nine cycles of the administration cycle occur. **Claim 4** The composition according to claim 1 or 2, wherein gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, is administered at a dose of 180 mg once a week. **Claim 5** The method further comprises administering to the human subject a CDK 4 / 6 inhibitor at least once a week for a period of three weeks; interrupting the administration of the CDK 4 / 6 inhibitor for a period of one week; resuming the administration of the CDK 4 / 6 inhibitor for at least one week after the interruption period; The composition according to claim 1 or 2, further comprising, wherein the cycle of administration and interruption of administration of the CDK 4 / 6 inhibitor is repeated at least two cycles. **Claim 6** The composition according to claim 5, wherein the step of administering the CDK 4 / 6 inhibitor occurs during the same week as the administration of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof.

7. The composition according to claim 5, wherein the CDK 4 / 6 inhibitor is selected from the group consisting of palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, libiciclib, and combinations thereof.

8. The composition according to claim 5, wherein the CDK 4 / 6 inhibitor is palbociclib.

9. The composition according to claim 8, wherein the palbociclib is administered at a dose of 125 mg per day.

10. The composition according to claim 5, wherein the method further comprises the step of administering an estrogen receptor antagonist to the human subject.

11. The composition according to claim 10, wherein the estrogen receptor antagonist is fulvestrant.

12. The composition according to claim 11, wherein the fulvestrant is administered at a dose of 500 mg every two weeks.

13. The composition according to claim 11, wherein the fulvestrant is administered at a dose of 500 mg every four weeks.

14. The composition according to claim 1 or 2, wherein the method further comprises the step of administering an estrogen receptor antagonist to the human subject.

15. The composition according to claim 14, wherein the estrogen receptor antagonist is fulvestrant.

16. The composition according to claim 15, wherein the fulvestrant is administered at a dose of 500 mg every two weeks.

17. The composition according to claim 15, wherein the fulvestrant is administered at a dose of 500 mg every four weeks.

18. A composition for use in a method of treating cancer in a human subject, comprising gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein the method comprises: selecting a human subject in need of treatment for cancer; administering to the human subject a therapeutically effective amount of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor, at least once a week for a period of three weeks; Discontinuing the administration of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and the CDK 4 / 6 inhibitor for a period of one week; After the discontinuation period, restarting the administration of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and the CDK 4 / 6 inhibitor at least once a week; comprising: wherein the administration over a period of at least three weeks and the administration interruption over a period of at least one week constitute one cycle, and the cycle is repeated at least two cycles, a composition.

19. The composition according to claim 18, wherein the restarted administration of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and the CDK 4 / 6 inhibitor occurs at least once a week for a period of three weeks.

20. The composition according to claim 18 or 19, wherein at least three cycles, at least four cycles, at least five cycles, at least six cycles, at least seven cycles, at least eight cycles, or at least nine cycles of the administration occur.

21. The composition according to claim 18 or 19, wherein gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, is administered at a dose of 180 mg once a week.

22. The composition according to claim 18 or 19, wherein the CDK 4 / 6 inhibitor is selected from the group consisting of palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, libiciclib, and combinations thereof.

23. The composition according to claim 18 or 19, wherein the CDK 4 / 6 inhibitor is palbociclib.

24. The composition according to claim 23, wherein the palbociclib is administered at a dose of 125 mg per day.

25. The composition according to claim 18 or 19, wherein the method further comprises administering an estrogen receptor antagonist to the human subject.

26. The composition according to claim 25, wherein the estrogen receptor antagonist is fulvestrant.

27. The composition according to claim 26, wherein the fulvestrant is administered at a dose of 500 mg every two weeks.

28. The composition according to claim 26, wherein the fulvestrant is administered at a dose of 500 mg every four weeks.

29. A composition for use in a method of treating cancer in a human subject, comprising gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein the method comprises: selecting a human subject in need of treatment for cancer; administering to the human subject a therapeutically effective amount of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor, at least once a week for a period of three weeks; interrupting the administration of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and the CDK 4 / 6 inhibitor for a period of one week; after the interruption period, restarting the administration of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and the CDK 4 / 6 inhibitor, at least once a week, wherein the administration for at least three weeks and the interruption of administration for at least one week constitute one cycle, and the cycle is repeated at least two cycles; administering an estrogen receptor antagonist to the human subject and comprising a composition.

30. The composition according to claim 29, wherein the restarted administration of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and the CDK 4 / 6 inhibitor occurs at least once a week for a period of three weeks.

31. The composition according to claim 29 or 30, wherein at least three cycles, at least four cycles, at least five cycles, at least six cycles, at least seven cycles, at least eight cycles, or at least nine cycles of administration occur.

32. The composition according to claim 29 or 30, wherein gedatolisib is administered at a dose of 180 mg once a week.

33. The composition according to claim 29 or 30, wherein the CDK 4 / 6 inhibitor is selected from the group consisting of palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, libiciclib, and combinations thereof.

34. The composition according to claim 29 or 30, wherein the CDK4 / 6 inhibitor is palbociclib.

35. The composition according to claim 34, wherein the palbociclib is administered at a dose of 125 mg per day.

36. The composition according to claim 29 or 30, wherein the estrogen receptor antagonist is fulvestrant.

37. The composition according to claim 36, wherein the fulvestrant is administered at a dose of 500 mg every two weeks.

38. The composition according to claim 36, wherein the fulvestrant is administered at a dose of 500 mg every four weeks.

39. The composition according to any one of claims 1, 2, 18, 19, 29, and 30, wherein the cancer is a solid cancer.

40. The composition according to claim 39, wherein the solid cancer is selected from the group consisting of breast cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, prostate cancer, testicular cancer, penile cancer, lung cancer, colorectal cancer, melanoma, bladder cancer, brain / CNS cancer, esophageal cancer, gastric cancer, head / neck cancer, kidney cancer, liver cancer, pancreatic cancer, and sarcoma.

41. The composition according to claim 39, wherein the solid cancer is a hormone-dependent cancer.

42. The composition according to claim 41, wherein the hormone-dependent cancer is selected from the group consisting of breast cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, prostate cancer, testicular cancer, and penile cancer.

43. The composition according to claim 41, wherein the hormone-dependent cancer is breast cancer.

44. The composition according to claim 43, wherein the breast cancer is metastatic, hormone-resistant, estrogen receptor-positive, estrogen receptor-negative, progesterone receptor-negative, progesterone receptor-positive, triple-negative, HER2-positive, or HER2-negative breast cancer.

45. The composition according to claim 43, wherein the breast cancer is of the basal or luminal subtype.

46. The composition according to any one of claims 1, 2, 18, 19, 29, and 30, wherein the human subject is a premenopausal or postmenopausal female patient.

47. The composition according to any one of claims 1, 2, 18, 19, 29, and 30, wherein the human subject has failed a prior treatment for cancer during a period of less than 12 months.

48. The composition according to any one of claims 1, 2, 18, 19, 29, and 30, wherein the human subject has failed a prior treatment for cancer during a period of less than 6 months.

49. The composition according to any one of claims 1, 2, 18, 19, 29, and 30, wherein the human subject has failed two or more prior treatments for cancer.

50. The composition according to claim 47, wherein the prior treatment that failed is an endocrine treatment for cancer.

51. A composition for use in a method of treating cancer in a human subject, comprising a CDK 4 / 6 inhibitor, wherein the method comprises: selecting a human subject in need of treatment for cancer; administering to the human subject a therapeutically effective amount of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor, at least once a week for a period of 3 weeks; interrupting the administration of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and the CDK 4 / 6 inhibitor for a period of 1 week; and after the interruption period, restarting the administration of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and the CDK 4 / 6 inhibitor, at least once a week. comprising wherein the administration for at least 3 weeks and the administration interruption for at least 1 week constitute one cycle, and the cycle is repeated at least 2 cycles, characterized in that the composition.

52. A combination for use in a method of treating cancer in a human subject, comprising gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor, wherein the method comprises: selecting a human subject in need of treatment for cancer; administering to the human subject a therapeutically effective amount of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and a CDK 4 / 6 inhibitor, at least once a week for a period of 3 weeks; The step of interrupting the administration of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and the CDK 4 / 6 inhibitor for a period of one week; After the interruption period, the step of restarting the administration of gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, and the CDK 4 / 6 inhibitor at least once a week; comprising; A combination, characterized in that the administration over a period of at least three weeks and the interruption of administration over a period of at least one week constitute one cycle, and the cycle is repeated at least two cycles.